The invention relates generally to stents and more particularly to a drug delivery endovascular stent which delivers a specific immunosuppressant drug to the stent treatment site.
Stents are a widely used adjunct to coronary artery interventions. After an angioplasty or other intervention, a stent may be introduced to the treatment site to support the wall of the artery.
The principle problem with stent usage is a re-closure process called restenosis. The problem of restenosis is widely recognized. It appears from research that the mechanisms for restenosis after a balloon procedure differs in detail from the healing processes associated with stent placement.
The biological reactions associated with the use stents causes a cascade of cellular growth and proliferation. The mechanical action of the stent against the artery wall (spring back) and the introduction of the foreign substance into the body results in an inflammatory response which gives rise to signaling molecules called cytokines which mediate a variety of biologic processes. Although the magnitude and course of the inflammatory response varies widely among patients, the body isolates the foreign material of the stent by encapsulating it with cell growth. Consequently a pseudo intima will be produced on the surface of the stent. In general the propagation of a smooth muscle tissue pseudo intima is desirable, however in some patients the proliferation of smooth muscle cells and their conversion to secretory muscle cells results in re-closure of the vessel within a short period of time. Although this is a normal response to the insertion of a foreign body, given the location of the stent it results in severe clinical problems. Other short term complications exist as well including acute thrombosis. The delivery of anti platelet drugs and other thrombolytic drugs have been proposed to treat this near term type of reclosure.
Several efforts have been made to prevent or delay the longer term restenosis process. One approach has been to implant radioactive stents where the local emission of beta radiation inhibits hyperplasia. Although intracoronary radiation is effective at preventing restenosis this grossly interferes with the healing process previously described and can lead to secondary complications such as edge restenosis and late thrombosis. One example of this stent technology is known from U.S. Pat. No. 5,871,437 to Alt. This reference teaches the use of multiple coating on the stent substrate. One coating carries a beta emitter while other coatings deliver a anticoagulation drug.
Another approach to the treatment of acute thrombosis in stent treatments is discussed in U.S. Pat. No. 5,788,979 to Alt et al. The stent according to this invention uses a biodegradable coating to release a controlled amount of a therapeutic agent such as an a anti-coagulant, anti-thrombogenic, or antistenotic drug. The biodegradable coating provides a local release of drug which improves the bio-compatibility of the stent and reduces inflammation and the hyperplasia processes. The objective or these different methods is to interfere with and control the proliferation of the smooth muscle cells.
Although the various coated stents improve the restenosis rates for some patients, a fully bio-compatible stent remains an elusive problem as the factors of local thrombus formation, vessel injury and inflammation interact in complex and individually variable ways. For these reasons re-occlusion and restenosis problems are difficult to manage in a clinical setting. Restenosis remains a significant risk for patients.
In contrast to the prior art, the stent of the present invention delivers an effective dose of the immunosuppressant drug tacrolimus to the stent treatment site. The tacrolimus is delivered at a rate and in a concentration that both encourages proliferation of smooth muscle cells and limits conversion of such cells to the secretory type muscle cells. This method and approach differs from the prior art cytostatic techniques where Taxol and related drugs are used in an overall strategy to interfere with and delay the healing response.
In accord with the method and device of the of the present invention a stent delivers tacrolimus to the cells proliferating on the surface of the stent. The stent forms a primary structure and the coating is a secondary process. In general it is preferred to use a polymer coat but surface modification of the stent itself to create a drug delivery surface is possible though not preferred.
The preferred device delivers drug by elution from a polymer matrix applied as a coating to the stent. The polymer matrix may be permanent and non biodegradable or it may be biodegradable. An example of a suitable biodegradable material is polylactic acid (PLA). Examples of more permanent matrix materials includes; polyethylene; vinyl acetate and medical polyurethanes and silicone rubber. Other biodegradable and non-biodegradable materials are contemplated within the scope of the inventions well. The primary requirement is the formation of a biocompatible matrix to allow elution of the tacrolimus.
The localized and selective delivery of the tacrolimus and tacrolimus containing compounds encourages endothelization of the stent with smooth muscle cells and other endothelial cells and discourages the proliferation and conversion of such cells to secretory smooth muscle cell types.
The beneficial effect of tacrolimus and its analogues is unknown in this context and the drug is not indicated for or labeled for use in cardiovascular interventions.
Although arterial endovascular and specifically coronary interventions are an important application for this invention it should be recognized that other biomedical devices and device locations, sizes and drug concentrations are contemplated within the scope of the invention. It must also be recognized that additional features and structures may be added to the invention without departing from the scope of the invention.